Withania somnifera (Ashwagandha) is a very revered herb of
the Indian Ayurvedic system of medicine. It is useful for treating
various kinds of disease processes and especially used as a nervine
tonic. Withania somnifera (Ws) contain a wide array of active
components including withaferin A, withanone and other flavonoids
exhibiting strong anti-oxidant properties. Many scientific studies on
Ws were carried out previously that showed its anti-oxidative effect,
synergistic effect with other medicinal herbs and its efficiency to
increase catecholamines level and regulation of apoptotic processes.
Furthermore, treatment of Parkinsonian mice models with Ws has
shown neuroprotection of dopaminergic neurons in substantia nigra
pars compacta region of mid-brain. The present review enlightens
the crucial role of Indian Ginseng to curb neurodegenerative disorder
such as Parkinson's disease. Extensive studies are needed to prove its
therapeutic efficacy in neuronal disorders.

Ashwagandha (Withania somnifera, fam. Solanaceae) is
popularly known as "Indian Ginseng" or "Indian Winter cherry"
[1,2]. It is an indigenous medicinal plant exhibiting a vital role in
the treatment of various diseases such as stress [3], anxiety [4],
arthritis [5] and other disorders related to the central nervous
system (CNS) such as Parkinson's [6,7] and Alzheimer's disease
[8]. In Ayurveda, the Indian system of medicine, use of herbal
plant extracts for treating PD has been well documented by [9]
in clinical model. Gupta LG and Rana AC. 2007., [10] stated that
whole plant, roots, stem, leaves, seeds and fruits of Ws were
used for various experimental studies in order to elucidate their
therapeutic applications. Roots of Ws are the main portions
of the plant used therapeutically [11]. The dried roots of
Ashwagandha are found to be useful in the treatment of nervous
and sexual disorders [11,12]. The biological activity of Ws extract
showed antioxidant and free radical scavenging potential [13].
Additionally, Ws is a potent neuronal tonic and has been expected
to be used in the treatment of many neurological deficits including
epilepsy [14], poor memory [15], depression [4] and PD [6] in
animal model.

Parkinson's disease (PD) is the second most common
neurodegenerative disorder after Alzheimer's, affecting 1% of
the population by the age of 65 and 4–5% of the population by
the age of 85 [16,17]. Parkinson's disease is caused by the loss
of dopaminergic neurons in the substantia nigra pars compacta
region of mid-brain [18] resulting in the reduction of dopamine
level [19]. Various factors such as age, genetic and environmental
exposure are associated with the onset and progression of PD
[19,20].

In this review, we are focussing on the use of therapeutic
potential of Withania somnifera (Ashwagandha) in Parkinson's
disease. It possesses the power of combating neurodegenerative
disorder like PD. Nowadays, more emphasis is laid on the use
of medicinal herbs to treat human diseases. Therefore, the
cornerstone of this review paper is to focus on how Ashwagandha
alleviates Parkinson's disease.

Chemical Constituents

Rastogi RP and Mehrotra BN 1998.,[21] has revealed over
35 chemical constituents contained in the roots of Ashwagandha
through laboratory analysis. The roots of Ws possess withanolides,
which are steroidal in nature and bear a resemblance, both in
their action and appearance, to the active constituents of the
plant Panax ginseng known as ginsenosides [11,12,22]. The
biologically active chemical constituents of Ws include alkaloids
(isopelletierine, anaferine, cuseohygrine, anahygrine, etc.) and
steroidal lactones (withanolides, withaferins) [23]. Ganzera
M, Chodhary MI and Khan IA. 2003.,[24] investigated two
withanolides of Ws, withaferin A and withanolide D through
HPLC analysis. Other constituents of Ws include saponins
containing an additional acyl group (sitoindoside VII and VIII),
and withanoloides with a glucose at carbon 27 (sitoindoside IX
and X) [24,25]. Matsuda H, et al.2001, [26] isolated and identified
seven new withanolide glycosides of Ws called withanosides I, II,
III , IV, V, VI and VII.

Pharmacological effects of Withanolides

Withania somnifera possesses multiple pharmacological
properties which are mainly accredited to the withanolides, its
active constituents [7]. Medicinally, Ws root extract is known to possess anti-aging [27], anti-oxidant [6] and anti-cancerous
properties [28]. Andallu B and Radhika B.2000., [2] demonstrated
through clinical observation that roots of Ws are a potential source
of hypoglycemic, diuretic and hypocholesterolemic agents.
Sitoindosides VII–X and Withaferin-A, the two active principles
of Ashwagandha, have been shown to have significant antistress
activity when tested in diverse spectrum of stress-induced
paradigms [29] and also reported to exhibit strong anti-oxidant
activity in rat model [30]. The withanolides serve as hormone
precursors that may get converted into human physiologic
hormones as needed [22]. According to Ahmed M et al.2005.,
[31] pretreatment with Ws extract was found to prevent all
the changes in antioxidant enzyme activities, catecholamine
content, dopaminergic D2 receptor binding and tyrosine
hydroxylase expression in PD rat model (Parkinson's induced
by 6-hydroxydopamine (6-OHDA)) in a dose-dependent manner.
Thus, Ws seems to exert its pharmacological effect by occupying
the receptors on the cell membrane and thereby, preventing the binding of actual hormone in a concentration dependent manner.
Kobuyama T et al.,2002 [32] illustrated therapeutic potential of
withanolide A isolated from root of Ws, that possess ability to
regenerate neurites and reconstruct synapses in severly damaged
neurons in mice. Amongst withanolides of Ws, withaferin A, a
major component of biologically active steroids, showed potent
anti-inflammatory [33] and anti- cancerous activity [34]. Thus,
the study revealed the pharmacological potential of Ws, which
could be harnessed in future, for the therapeutic approaches to
PD.

Scientific work done on Withania Somnifera for
treating PD

Effect of Ws on Oxidative stress

Impaired anti-oxidative defence mechanisms and increased
generation of oxidative free radicals, have been implicated in the
neurodegenerative conditions like PD. Superoxide dismutase
(SOD), catalase (CAT) and glutathione peroxidase (GPX) are the
major free radical scavenging enzymes. Defective functioning of
these enzymes leads to accumulation of toxic free radicals and
consequent degenerative progression of the disease [35]. The
active glycowithanolides of Ws were found to elevate the cortical
and striatal concentrations of the anti-oxidant enzymes, SOD,
CAT and GPX [30]. Manjunath MJ and Murlidhara.2013.,[7]
investigated the neuroameliorative effects of Ws in a rotenone
(ROT) model of Drosophila melanogaster (Oregon-K). Significant
protection was conferred by Ws against ROT-induced lethality,
while the survivor flies exhibited improved locomotor phenotype.
Furthermore, biochemical investigations revealed that ROTinduced
oxidative stress was significantly diminished by Ws.
6-Hydroxydopamine (6-OHDA) is one of the most widely used rat
models for Parkinson's disease eliciting its toxic manifestations
through oxidative stress. The anti-parkinsonian effect of Ws
extract was evaluated and reported to have potent anti-oxidant,
anti-peroxidative and free radical quenching properties in
various diseased conditions. Ws extract was found to reverse
levels of reduced glutathione, GPX, SOD and CAT significantly in a
dose-dependent manner as compared to 6-OHDA rat model [31]. Also Prakash J et al.2013., [13] stated through their work about
the neuroprotective function of Ws root extract against Maneb-
Paraquat (MB-PQ) induced dopaminergic neurodegeneration, in
PD mice model. According to their work, Ws extract is capable of
inhibiting the oxidative stress occurring in nigrostriatal tissues
and simultaneously increasing the count of Tyrosine Hydroxylase
positive cells in SN region of the MB–PQ induced PD mice brain.
Henceforth, Ws comprehend strong antioxidant potential and
its ROS scavenging property plays an important role in the
prevention of PD by defying neurodegeneration.

Synergistic Effect of Ws

Girdhari LG and Avtar CR.2009.,[36] worked on synergistic
effect of Ws and L-dopa in the inhibition of haloperidolinduced
catalepsy in mice. The anti-cataleptic effect of Ws
could be attributed to polyphenols present in it responsible
for direct scavenging of free radicals and also by inhibition
of lipid peroxidation in the central nervous system. Ws and
Mucuna pruriens (Mp) are traditional herbal plants known to
have neuroprotective effects due to the presence of L-DOPA in
Mp seed powder and withanoloides in Ws root extract [37].
Hence, the synergistic effect of Ws and Mp in Parkinsonian
mice induced by chronic exposure to 1-methyl-4-phenyl
1,2,3,6-tetrahydropyridine (MPTP) [38] and Paraquat (PQ),
Prakash J et al.2013.,[37] was examined and all the neurochemical
variables, oxidative stress and physiological abnormalities were
found to be significantly improved compared to untreated PD
mice brain. According to Prakash J et al.2013., [37] exposure
to PQ increases nitrite content in the nigrostriatal region.
Therefore, they established through their work that Mp + Ws coexposure
amends the level of nitrite in PQ treated mice and this
decline in nitrite content by Mp + Ws might be attributed to the
antioxidant property of Mp [39] and Ws [1] plant extracts. Also,
Malondialdehyde (MDA) a product of lipid peroxidation has been
used as a marker of oxidative damage [13]. Prakash J et al.2013.,
[37] enlightened through their work that after treatment of
mice with PQ, the MDA level was highly increased compared to
controls. However, MDA levels were significantly ameliorated
after the Mp + Ws co-treatment. Thus, the combined treatment of
Mp + Ws showed a significant effect as compared to Mp and Ws
treatments alone.

Therefore, the pioneer work done on synergisitic effect of
Ws with Mp and Ws with L-Dopa respectively infered about the
efficacy of Ws for treating PD.

Effect of Ws on Catecholamines level

The neurotransmitter, Dopamine (DA) plays a key role
in motor control and body movement. Oxidative stress and
reduced levels of catecholamines are the contributing factors
of neurodegeneration in PD [40] and this leads to the loss
of motor function in PD patients [41,42]. RajaSankara S et
al.2009., [43] analysed catecholamines such as dopamine (DA),
3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic
acid (HVA) in the Ws treated and untreated PD mice striatum.
According to Rajasankara, oral treatment of PD mice with Ws
root extract (100 mg/kg body weight) for 7 days or 28 days elevated DA, DOPAC and HVA levels in the corpus striatum.
Thus, through their work they deduced the medicinal benefit of
the Indian traditional herb Ws which enhances catecholamines
and antioxidants and prevents lipid peroxidation in the corpus
striatum of PD mice. Prakash J et al.2014., [6] studied the effect
of Ws on dopamine and its metabolites in the SN region of PD
mice. Reduction of dopamine and its metabolites was found in PD
mice brain as compared to controls. Further, treatment with Ws
for 9 weeks significantly improved dopamine, DOPAC, and HVA
levels as compared to untreated PD mice. Hence, it is clear that
Ws holds a competency to elevate catecholamines level and fight
against PD like disorders.

Effect of Ws on Apoptotic Pathways

Apoptosis or programmed cell death is a tightly regulated
process resulting in the active suicide of cells under a particular
set of circumstances. It has been found that one of the main
causes of neurodegenerative diseases is the defective regulation
of programmed cell death [44]. Bcl-2 is an anti-apoptotic protein
that suppresses cell death by inhibiting the action of a proapoptotic
protein, Bax. Thus, the Bcl-2 and Bax ratio decides
whether a cell will survive or succumb to apoptosis. Interestingly,
it has been suggested in a study that over expression of Bcl-2 helps
to attenuate MPTP-induced neuronal cell death [45]. Prakash J
et al.2014., [6] showed that Bcl-2 expression was significantly
down regulated while Bax expression was significantly elevated
in a MB-PQ model of PD. Furthermore, it was observed that Ws
treatment increased the level of anti-apoptotic (Bcl-2) proteins
and decreased the level of the pro-apoptotic (Bax) proteins in the
MB–PQ model of PD. Thus, the Indian Ginseng (Ashwagandha) has
been emerged with its capability to regulate the level of apoptotic
proteins Bcl-2 and Bax respectively. Henceforth, it is clear that
Ws owns the ability to overcome neurological disorders like PD.

Discussion and Conclusion

The present study supports the fact that Ashwagandha is a
potent neuroprotective agent and hence, plays a significant role in
ameliorating Parkinson's disease, a neurodegenerative disorder.
This review paper delineates the potential of Ws to oppose
oxidative damage and decline in catecholamines level and also
how it exhibits synergistic effect with Mp and its role in regulation
of apoptotic proteins Bcl-2 and Bax. The above discussion clearly
outlines the efficiency of Ws to eradicate oxidative stress which
is one of the major contributing factor in PD. Thus, the traditional
use of Indian Ginseng has a logical and scientific basis which can
be exploited in the research area related to PD. Moreover, clinical
studies on large scale are needed to prove the efficacy of this
herb, especially in PD and other neuronal disorders.

Acknowledgement

Authors are sincerely thankful to Department of Biochemistry,
Institute of Science, Banaras Hindu University, Varanasi for
providing us the platform to streamline our basic skill and
knowledge in this field and to come up with more innovative
ideas in research related to Parkinson's disease in Neurobiology
Lab.